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Structure-activity relationships of trans-substituted-propenoic acid derivatives on the nicotinic acid receptor HCA2 (GPR109A)

van Veldhoven, J P D; Blad, C C; Artsen, C M; Klopman, C; Wolfram, D R; Abdelkadir, M J; Lane, J R; Brussee, J; IJzerman, A P

Authors

J P D van Veldhoven

C C Blad

C M Artsen

C Klopman

D R Wolfram

M J Abdelkadir

ROB LANE Rob.Lane@nottingham.ac.uk
Associate Professor

J Brussee

A P IJzerman



Abstract

Nicotinic acid (niacin) has been used for decades as an antidyslipidemic drug in man. Its main target is the hydroxy-carboxylic acid receptor HCA2 (GPR109A), a G protein-coupled receptor. Other acids and esters such as methyl fumarate also interact with the receptor, which constituted the basis for the current study. We synthesized a novel series of substituted propenoic acids, such as fumaric acid esters, fumaric acid amides and cinnamic acid derivatives, and determined their affinities for the HCA2 receptor. We observed a rather restricted binding pocket on the receptor with trans-cinnamic acid being the largest planar ligand in our series with appreciable affinity for the receptor. Molecular modeling and analysis of the structure-activity relationships in the series suggest a planar trans-propenoic acid pharmacophore with a maximum length of 8 Å and out-of-plane orientation of the larger substituents.

Citation

van Veldhoven, J. P. D., Blad, C. C., Artsen, C. M., Klopman, C., Wolfram, D. R., Abdelkadir, M. J., …IJzerman, A. P. (2011). Structure-activity relationships of trans-substituted-propenoic acid derivatives on the nicotinic acid receptor HCA2 (GPR109A). Bioorganic and Medicinal Chemistry, 21(9), 2736-2739. https://doi.org/10.1016/j.bmcl.2010.11.091

Journal Article Type Article
Acceptance Date Nov 19, 2010
Online Publication Date Nov 25, 2010
Publication Date May 1, 2011
Deposit Date Apr 22, 2020
Journal Bioorganic and Medicinal Chemistry
Print ISSN 0968-0896
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 21
Issue 9
Pages 2736-2739
DOI https://doi.org/10.1016/j.bmcl.2010.11.091
Public URL http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=21167710&retmode=ref&cmd=prlinks
Publisher URL https://www.sciencedirect.com/science/article/abs/pii/S0960894X10017166